Method and apparatus for releasing a controlled amount of aerosol medication over a selectable time interval

ABSTRACT

A portable, battery powered, hand-held system for releasing a controlled dose of aerosol medication for inhalation by a patient including a durable body and a medication cassette inserted in the durable body. The cassette includes a housing for containing a canister of medication, bears an identification code, and permits the canister to be manually depressed to release a dose, e.g., a metered dose, when out of the durable body. The durable body includes an actuator mechanism for engaging an inserted cassette and its canister, and an actuator release mechanism for controlling the actuator mechanism to depress the canister for a selected period of time to release the desired dose of medication and then the release the canister. The actuator mechanism, includes a compression spring for depressing the canister and a torsion spring for reloading the compression spring. The torsion spring is reloaded by rotating the cassette from an open position for delivering aerosol to a closed position. The actuator release mechanism includes a motor and trigger pin assembly that controls the release of the compression spring and the torsion spring, and, hence, the time that the canister is depressed. The motor operates in response to sensed flow satisfying a selected delivery threshold. The durable body includes a flow sensor having an asymmetrical orifice that is calibrated, independent of the cassette, to convert the sensed pressure due to flow into a flow rate. The orifice is separately calibrated for an inhalation flow rate range and an exhalation flow rate range over a selected number of known flow rates. The sensed pressure value is corrected for transducer offset drift and converted to a flow rate using the calibration data and piecewise linear interpolation.

This is a continuation of application Ser. No. 08/389,256, filed Feb.16, 1995, now U.S. Pat. No. 5,622,162; which is a continuation ofapplication Ser. No. 08/011,351, filed Jan. 29, 1993, now U.S. Pat. No.5,392,768, issued Feb. 28, 1995, which is a continuation-in-part ofapplication Ser. No. 07/664,758, filed Mar. 5, 1991, now U.S. Pat. No.5,404,871, issued Apr. 11, 1995.

This invention relates to improvements in the automatic delivery ofaerosolized compounds and medications for inspiration by patients, moreparticularly to a durable electronically controlled breath actuatedmetered dose inhaler device having replaceable medication cassettes.

BACKGROUND OF THE INVENTION

Known devices for delivering aerosol medication for inhalation by apatient include metered dose inhalers that are manually operated andbreath actuated. Breath actuated inhalers typically provide a metereddose automatically when the patient's inspiratory effort either moves amechanical lever or the detected flow rises above a preset threshold, asdetected by a hot wire anemometer. See, for example, U.S. Pat. Nos.3,187,748; 3,565,070; 3,814,297; 3,826,413; 4,592,348; 4,648,393;4,803,978; 4,896,832; a product available from 3M Healthcare known asAerosol Sheathed Actuator and Cap; and a product available from RikerLaboratories known as Autohaler. As used herein, references to "effort"and to "flow" are to the movement of air into and out of the patient'spulmonary system. The flow is typically detected as a flow rate (1/min),a flow volume (1), or a combination of a flow rate and flow volume ormore than one flow rate and/or more than one flow volume.

A major problem with manual metered dose inhalers is that the patientfrequently actuates the device at the incorrect time during inspiratoryflow, without inhaling, or during expiration and thus does not obtainthe benefits of the intended drug therapy. Accordingly, patients mayinspire too little medication, or take a second dose and receive toomuch medication.

One problem with breath activated drug delivery is that the dose istriggered on crossing a fixed threshold inspiratory effort. Thus, aninspiration effort may be sufficient to release a metered dose, but theinspiratory flow following the release may not be sufficient to causethe aerosol medication to pass into the desired portion of the patient'sairways. Another problem exists with patients whose inspiratory effortis not sufficient to rise above the threshold to trigger the releasevalve at all either all of the time or some of the time. This leads tofrustration and ineffective therapy.

The known metered dose inhalers include a canister and a body. Thecanister contains a reservoir of medication and aerosol propellant underpressure, a metering valve which includes a fixed size chamber thatcaptures a defined and uniform volume of material, and a valve stemwhich operates to release a metered dose. The metering chamber istypically maintained open to the reservoir. To release a dose, the valvestem is pushed into the metering valve. This causes the metering valve,in sequence, to close the chamber relative to the reservoir and capturea fixed volume of material under pressure, to open the chamber relativeto the valve stem to release the captured amount of material out aflowpath in the valve stem, to close the chamber relative to the valvestem, and then to open the chamber to the reservoir so that the chamberis positively refilled with medication/aerosol blend under pressure,providing the next dose to be administered.

The metered dose inhaler body contains a receptacle for the canister anda valve actuator (also referred to as a valve stem receptacle) thatcontains a flow path which terminates in a nozzle and receives the valvestem in alignment with the flow path. The nozzle is typically at anangle to the flow path and directs the released aerosol into thepatients' mouth (or nostril). The valve stem receptacle is typicallypassive. Thus, when the canister is pressed relative to the valve stemreceptacle, by manual or automatic advance, the valve stem is pressedinto the metering valve and causes the metered dose to be releasedthrough the flow paths in the valve stem and the valve stem receptacleand out the nozzle. Typically, the valve stem receptacle has africtional fit with the valve stem so that the canister is therebysecured to the body.

One problem with conventional pressurized meter dose canister devices isthat the metering chamber must be maintained open to the atmosphere fora period of time sufficient to release the entire dosage from thechamber. The required time period is a function of the interiordimensions of the valve stem, the valve stem receptacle, and the nozzle.Consequently, commercial manual metered dose inhalers are limited tovalves and medication formulations having release times less than abouta tenth of a second. This is so the patient is not burdened with havingto control the valve release time in addition to synchronizing therelease of medication with inspiration.

Metered dose inhalers also must be sufficiently agitated in order toobtain a homogeneous mixture of the medication and propellant blend forrefilling the metering chamber following administration of a dose. Aproblem with some breath actuated metered dose inhalers is that theiroperating sequence leaves the metering chamber open to the valve stemand the atmosphere and closed to the reservoir, rather than vice versa.Accordingly, the patient must reset or cock the inhaler to fill themetering chamber with a dose. If this occurs a period of time afterrelease of the last dose, or without sufficiently agitating the deviceprior to cocking, a non homogeneous mixture of medication and propellantmay be loaded into the metering chamber. This results in more or lessmedication being delivered to the patient than intended.

Another problem with existing metered dose inhalers, whether or notbreath actuated, is that the canisters and valve stem receptacles arefactory preset to deliver a fixed dose in a relatively short period oftime. This results in a given particle size distribution. Thatdistribution may not, however, provide a maximum or optional desiredrespirable fraction of the aerosol mist that is suitable for a desiredlocation of delivery of the medication in the particular patient. Theknown devices which attempt to solve this problem process the aerosolafter it is generated and thus are inefficient and wasteful. See, e.g.,U.S. Pat. No. 4,790,305, U.S. Pat. No. 4,926,852, U.S. Pat. No.4,677,975 and U.S. Pat. No. 3,658,059.

A problem with breath actuated metered dose inhalers that areelectronically controlled is that the actuators for pressing the metereddose canister consume considerable amounts of electrical power todeliver the force required to release a dose. Accordingly, they are notpractical for use as battery operated devices. See, for example, Newmanet al., Thorax, 1981, 36:52-55; Newman et al., Thorax, 1980, 35:234;Newman et al., Eur. J. Respir. Dis., 1981, 62:3-21; and Newman et al.,Am. Rev. Respir. Dis., 1981, 124:317-320 (the "Newman references").

It is well known that pulmonary functions, such as forced expiratoryvolume in one second, forced vital capacity, and peak expiratory flowrate, can be measured based on measured flow rates and used both todiagnose the existence of medical conditions, to prescribe medication,and to ascertain the efficiency of a drug therapy program. See, forexample, U.S. Pat. Nos. 3,991,404 and 4,852,582 and the Newmanreferences. Heretofore, these tests have been performed using availablespirometers. U.S. Pat. No. 4,852,582 also refers to using a peak flowrate meter to measure changes in peak flow rate before and afteradministration of a bronchodilator. The results of such tests before andafter administration of several different medications are used toevaluate the efficacy of the medications.

A problem with the foregoing pulmonary function test devices is thatthey are complicated. Another problem is that the test data must beexamined and interpreted by a trained medical practitioner to bemeaningful. Another problem is that they do not provide adequately foraltering the dosage of the medication administered in a single patientduring the course of therapy, or from patient to patient, using the samedelivery device for generating an aerosol of the same or differentmedications.

Another problem with the known techniques is that they do not meet theneeds for a portable device that is hand held, battery powered, andmeasures flow in two directions such that each direction has a differentrange of flow values with good resolution in each range.

SUMMARY OF THE INVENTION

The present invention relates to improvements on the basic inventionsset forth in U.S. application Ser. No. 07/664,758, the disclosure ofwhich is incorporated herein by reference in its entirety. It is anobject of this invention to provide improved apparatus, systems, andmethods for delivering aerosol compounds for inspiration by a patient.

It is another object of this invention to provide improved apparatus,systems, and methods for delivering for inspiration an aerosol having aparticle size distribution favorable for selective deposition intodesired locations in a patient's pulmonary system.

It is another object to release a controlled amount of aerosol during acontrollable and selectable time period, including a relatively slowrelease, to produce a metered dose having a selected particle sizedistribution and/or airway deposition location. It is another object toprovide a mechanism for releasing fully a metered dose over a selectedtime period. It is another object to maintain open the metering chamberof a metered dose inhaler for a selectable period of time sufficient torelease the full metered dose, and for refilling the metering valveimmediately following release. It is another object to provide a releasemechanism that can be programmed for a specific metering valve-nozzleemptying time. It is another object to deliver a metered dose ofmedication/propellant blend formulation having a slow release time.

It is another object of the invention to release automatically acontrolled amount of medication when the patient's detected inspiratoryflow exceeds a preselected or predetermined delivery threshold, and, ifthe detected flow does not exceed (or satisfy) the provided deliverythreshold, to determine a new delivery threshold based on a detectedflow parameter of the detected inspiratory flow not exceeding the priordelivery threshold, and to release a controlled amount of medicationover a controllable time period when a subsequently detected flowexceeds the new determined delivery threshold. The determined thresholdis thus recursively determined for each detected inspiratory flow notexceeding the previously established delivery threshold, whether thatthreshold is an initial preselected default triggering threshold, aninitial predetermined delivery threshold based on a calibration breath,or a subsequently determined threshold.

It is another object of this invention to provide an improved flowtransducer for measuring breath flow both for sensing inspiration todeliver aerosolized material for inspiration by a patient, and forsensing inspiration, expiration, and inspiratory and expiratory pausesfor measuring a patient's pulmonary function. It is another object toprovide variously for one or more of (1) varying the dosage orcontrolled amount of the aerosolized compound delivered for inspirationby the patient in response to detected changes in the patient'spulmonary function during a course of therapy directed to improvingpulmonary function, (2) providing an acuity display of the determinedpulmonary function to the patient, for example, to provide for alertingthe patient whether the patient's determined function indicates whetherthe patient should continue the inhalation drug therapy program or seekimmediate medical attention, and (3) monitoring changes in thedetermined pulmonary function.

It is another object to provide a flow transducer system that sensesflow passing in one direction over a first flow range and senses flowpassing in the other direction over a second flow range so that anoptimized resolution scale is obtained using the same processingelectronics for the different flow ranges in the different directions.

It is another object of the invention to provide for calibrating adurable flow transducer system having different flow sensing ranges indifferent flow directions. It is another object to calibrate such adurable flow transducer system with an array of data points spanning thetwo flow ranges and providing piecewise interpolation between datapoints.

It is another object of the present invention to provide a programmable,durable variable dose inhaler whereby the medication being administeredand the time release of medication can be selected, and the inhaler canbe programmed to provide for efficacious delivery of the selectedmedication to a given patient. It is another object to provide animproved inhaler with audible, visual or audiovisual feedback forprompting the patient to obtain a suitable breathing pattern fordelivering a selected medication at an appropriate time based on thepatient's detected inspiratory flow and, optionally, for measuring aselected pulmonary function.

It is another object of the invention to provide a durable, portable,battery-powered device for administering aerosolized medication having adisposable cassette containing the medication to be administered, and adurable body for receiving the cassette, the body having a calibratedflow transducer system, an actuator mechanism device for releasing adose of medication from the cassette, an actuator release mechanism foractuating the actuator mechanism in response to the sensed flowsatisfying the provided delivery threshold, and control electronics.

It is a further object of the present invention to provide a disposablecassette of medication with an electronic circuit or other code foruniquely identifying the cassette, including the type of medicationcontained therein. It is another object to provide such a cassette witha nonvolatile memory device and optionally a power supply.

It is another object of the invention to provide a durable, portable,battery powered device for delivering aerosolized medication including auniquely coded disposable cassette and a durable body having a circuitfor reading the cassette code to identify the cassette and/or themedication to be delivered.

It is another object to provide a disposable mouthpiece containing anozzle for dispensing medication, and a non-disposable flow rate sensorlocated in the flow path to detect flow which does not interfere withgeneration of an aerosol for inspiration by a patient.

It is another object of the invention to provide for determiningvariations of the flow rate sensor output unrelated to variations inflow over time and to correct such variations. It is another object toprovide drift offset correction of a flow transducer output in real timeduring operation.

The aforementioned U.S. patent application Ser. No. 664,785, copendingand commonly assigned, provides methods and apparatus for delivery ofaerosol medications for inspiration which increases the effectivenessand utility of devices for delivering aerosolized medications and whichovercomes many problems of the prior known devices. That applicationconcerns methods and apparatus based on detecting the patient'sinspiratory flow and releasing a controlled amount of an aerosolmedication as one or more pulses at one or more corresponding identifiedpoints in the detected inspiratory flow, to provide an efficaciousdelivery of a selected amount of medication.

Each pulse may be provided with a pulse width, shape, and frequency thatwill provide the respirable fraction of the aerosolized compound beingdelivered and the cumulative particle size distribution so as to enhancedelivery of the aerosolized compound to desired loci in the airway. Thetime the valve is opened is selected to produce an aerosol mist having acumulative particle size distribution selectively favoring small orlarge particles, as desired. The time open is selectable between 10 and1000 msec. The valve may be operated asynchronously or synchronously toproduce one or more pulses such that each full dosage of aerosolincludes one pulse or more than one pulse of non-uniform or uniformpulse widths, shapes, and intervals between pulses.

The delivery threshold may be based on an inspiratory flow rate, moreparticularly, a selected rate prior to the occurrence of the peakinspiratory flow rate, e.g., for a preselected threshold a rate in therange of 20 to 30 liters per minute, an inspiratory flow volume, e.g.,for a preselected threshold a volume of about 1.0 liter. Morepreferably, the delivery threshold is a combination of a flow rateparameter and a flow volume parameter as, e.g., a pair.

The U.S. application also refers to methods and an apparatus fordelivering an aerosol from a supply of aerosol generating material forinspiration by a person in response to the detected inspiratory flow ofthe person. One such apparatus includes:

a valve in communication with the supply of aerosol generating material;

means for operating the valve to release an amount of aerosol generatingmaterial to form an aerosol;

means for detecting an inspiratory flow of the person;

means for controlling the valve operating means in response to thedetected inspiratory flow comprising:

first means for determining whether each detected inspiratory flow isone of a first flow or a subsequent flow, the first flow correspondingto one of the first attempt to deliver an amount of aerosol and thefirst attempt to deliver an amount of aerosol following delivery of anamount of aerosol, the subsequent flow corresponding to an inspiratoryflow detected subsequent to a preceding detected inspiratory flow notfollowed by delivery of an amount of aerosol;

means for providing a delivery threshold corresponding to a point in thedetected inspiratory flow at which an amount of aerosol is to bedelivered, the provided delivery threshold being a preselected deliverythreshold in response to the detected inspiratory flow being determinedto be a first flow, and a determined delivery threshold in response tothe detected inspiratory flow being determined to be a subsequent flow,the providing means including means for calculating the determineddelivery threshold based on the preceding detected inspiratory flow; and

second means for determining whether or not the detected inspiratoryflow satisfies the provided delivery threshold so that the controllingmeans operates the valve to deliver an amount of aerosol in response tothe second determining means determining that the detected inspiratoryflow satisfies the provided delivery threshold.

The calculating means and method step for providing the determineddelivery threshold determine the delivery threshold based on thedetection of an inspiratory flow not satisfying the provided deliverythreshold, and can determine recurvisely new delivery thresholds foreach successive detected inspiratory flow that fails to satisfy eachprovided delivery threshold. This may be obtained by measuring aselected flow parameter of the detected inspiratory flow and adjustingthe selected delivery threshold in response to the measured flowparameter. The selected flow parameter may be a point corresponding tothe detected maxima of flow rate, flow volume, or some combination offlow rate and flow volume, such that the adjustment is a percentage ofthe detected flow parameter.

A reset flow event is declared on initialization of the system andfollowing delivery of an aerosol in response to a sensed first flow orsubsequent flow satisfying a provided threshold. It also may be declaredafter a preset time interval. A sensed flow following a reset flow eventis treated as a first flow. Thus, a reset flow event separatessuccessive attempts to deliver a controlled amount of a medication.

The U.S. application also discloses an embodiment in which thepreselected delivery threshold is initially determined based on theperson's measured inspiratory flow which is sensed as a calibrationbreath, and not as an attempt to deliver medication. The attempt todeliver medication is made when a subsequently detected inspiratory flowis detected and compared to the determined delivery threshold.Thereafter, the delivery is made if the detected flow satisfies thepredetermined delivery threshold, and the delivery threshold isrecursively lowered as in the aforementioned embodiment, i.e., based onthe flow parameter of the preceding failed attempt, if any subsequentlydetected flow fails to satisfy the threshold. A preselected deliveryschedule, corresponding to the optimal delivery threshold (andoptionally additional delivery points) for the administration of theselected aerosol medication also may be determined based on the measuredinspiratory flow parameters.

The means for detecting the inspiratory flow for release of medicationis a tube defining an inspiratory flow path having a mouth end and anopen end and a flow transducer disposed in the flow path. The flowtransducer may be selected from among a flow resistive device orstructure which generates a pressure drop across the device (referred toas a differential pressure transducer or structure) and an associatedmeans for converting the measured differential pressure into aninspiratory flow rate, e.g., a pneumotach, a hot wire anemometer andmeans for converting the measured temperature changes into aninspiratory flow rate, and similar devices for providing a flow ratesignal. The inspiratory flow path may include a means for providing alaminar flow through the inspiratory flow path so that the flowtransducer detects the differential pressure across a laminar air flow.The laminar flow provides a flow and a flow path having linearcharacteristics for converting the differential pressures to flow rate.In embodiments not having a laminar flow means or using structures,transducers and/or inspiratory flow paths not having such linear flowcharacteristics, such as venturi ports or a single resistive flowscreen, the flow path may be encoded by an array of predeterminedcalibration constants. Thus, nonlinear characteristics of thedifferential pressures detected across the flow resistive device may beconverted by use of the calibration constant array for the range ofpressures detected to flow rates, directly or indirectly. Differentialpressure transducers having a differential pressure sensitivity in therange of ±25.4 cm of water corresponding to a flow rate of from about 0to about 800 liters per minute, are described.

The U.S. application also describes methods and apparatus for monitoringthe patient's breath flow patterns during the course of an aerosolizedmedication inspiration therapy program and determining the patient'spulmonary function, e.g., forced expiratory volume in one second, forcedvital capacity, and peak expiratory flow rate, based on detected breathflow. The same flow transducer used for inspiration flow sensing also isused for measuring pulmonary function. A display device is provided fordisplaying the patient's determined pulmonary function quantitativelyand/or qualitatively. The display device may be used to indicate thepatient's instantaneous condition when an instantaneous pulmonaryfunction is measured. The display device also may be used to indicaterelative changes in condition when a subsequent measure of the pulmonaryfunction is compared to a prior measure (or to a historical average ofthe measures, e.g., a weighted average) of that pulmonary function. Theapparatus also may be configured to acquire a second measure ofpulmonary function, compare that measure to a prior measure, and displaytrend data to the patient, thereby to indicate whether the person'smedical condition is improving, degrading, or remaining about the same.Importantly, this display will indicate to the patient when measuredfunctions indicate that the patient should seek medical attention.

The relative changes in measured pulmonary function may be used toadjust the dosage of medication based on the determined changes in thedetermined function. This may occur based on a relative changedetermined from one administration of medication to the next, or from abaseline measured pulmonary function (or a weighted average historicalrecord) to the next administration of medication.

The method also includes acquiring a second breath parameter subsequentto the previously measured pulmonary function and measuring a secondpulmonary function, comparing the second measured pulmonary function tothe first measured pulmonary function, indicating whether or not thepatient's determined pulmonary function has changed from the first tothe second determinations, providing a first, second, and third visualindicators, and displaying whether the second measured pulmonaryfunction has improved on the first visual indicator, remained nominallythe same on the second visual indicator, and degenerated on the thirdvisual indicator, relative to the previously measured pulmonaryfunction.

It should be understood that, in the context of comparing two measuredpulmonary functions; the term first breath flow or first detectedpulmonary function may be one of the previously acquired measurement, abaseline measurement made at the beginning of the medication therapy,and a changing weighted average of previously acquired measurements,whereby the weights may be selected to favor more recently acquired orless recently acquired measurements. Thus, the latter acquiredmeasurement may be compared to such a first measurement for indicatingshort term relative changes, absolute changes from a baseline, or morelong term relative changes.

The U.S. application also refers to a portable, hand held, batteryoperated device for use in delivering aerosolized medications to apatient and monitoring pulmonary functions, recording pertinentinformation such as a calendar log of sensed flow parameters, amounts ofaerosol administration together with a signal corresponding to thesensed flow parameter triggering the release, and pulmonary function.

Broadly, the present invention is directed to improvements in theconstruction and operation of a portable, hand-held device fordelivering aerosol medication.

In one respect, the invention is directed to apparatus and methods forreleasing a controlled amount of medication over a selected timeinterval in response to a sensed flow satisfying a provided deliverythreshold for use in a battery powered hand held device. In a preferredembodiment, the metering valve and nozzle combination is controlled touse a slow release nozzle, i.e., a release time that is longer than the0.1 second release time of conventional metered dose canisters, e.g., onthe order of about a quarter second, two seconds, or more.

One such apparatus for providing a timed release of an amount of aerosolmedication comprises:

a flow sensor for detecting inspiratory flow;

a canister of medication having a body and a valve stem, the valve stembeing spring biased closed and depressible relative to the canister bodyto open and release a dose of aerosol medication;

a housing having valve stem receptacle for receiving the valve stem anda nozzle for releasing an aerosol into an inhalation flow path, thevalve stem receptacle having an inner dimension terminating in thenozzle;

a drive element for depressing the canister body relative to the valvestem receptacle, thereby to release a dose of aerosol medication; and

a release actuator for moving the drive element to depress the canisterbody relative to the valve stem receptacle and maintain the bodydepressed for a selected period of time so that a controlled dose ofmedication is released through the valve stem receptacle inner dimensionand out the nozzle.

Another aspect of the invention is directed to apparatus and methods forcontrolling the position of a mechanism for use in holding the driveelement depressed for the selected time. One such apparatus uses a plateto restrain the movement of a trigger pin being urged away from thedriver element, by a biasing force.

Another aspect of the invention is directed toward methods and apparatusfor controlling movement of a plate acted on by a force exerting objecthaving a variable force between a range of motion along an axis. Onesuch apparatus comprises:

a lead screw having a multi-start thread;

a motor connected to the lead screw for rotating the lead screw in agiven direction;

a plate having a first surface for contacting the object and a secondsurface for engaging a thread of the lead screws;

a spring having a second force operatively connected to the plate forurging the plate toward the object and a first end of the range ofmotion so that when the force exerted by the object is less than theforce exerted by the spring the plate is moved away from the motor tothe first end of the range of motion, and when the force exerted by theobject is greater than the force exerted by the spring, the plate secondsurface engages in the thread of the lead screw, wherein the distancebetween the starts of the multi-start thread controls the positionresolution of the return spring at the first end of the range of motion.

One such method comprises:

providing a motor having a multi-start thread lead screw; providing theplate with an edge for engaging a thread of one of the multi-startthreads of the lead screw;

biasing the plate to move away from the motor to a first location alongthe lead screw with a spring having a force when the force of the forceexerting object is less than the spring force;

engaging the plate edge in the lead in response to the force of theforce exerting object being greater than the spring force;

operating the motor to retract the plate along the lead screw towardsthe motor to a second location in response to the force of the forceexerting object; and

returning the plate to a third location in response to the force of theforce exerting object decreasing below the spring force, wherein thedistance between the first and third locations is less than the distancebetween adjacent starts of the multi-start thread.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features of the invention, its nature and various advantageswill be more apparent from the accompanying drawings and the followingdetailed description of the invention, in which like reference numeralsrefer to like elements and parts, and in which:

FIG. 1 is an elevated perspective view of an aerosol delivery device inaccordance with a preferred embodiment of the present invention;

FIG. 2 is a view of the device of FIG. 1 with the mouthpiece closed;

FIG. 3 is a cross-sectional view taken along line 3--3 of FIG. 1;

FIG. 3A is a top view of the mouthpiece of FIG. 1;

FIG. 3B is a side sectional view taken along line 3B--3B of FIG. 3A;

FIG. 3C is a rear sectional view taken along line 3C--3C of FIG. 3B;

FIG. 4 is an elevated perspective view of the replaceable cassette ofFIG. 1;

FIG. 5 is an exploded view of the replaceable cassette of FIG. 4;

FIGS. 6-10 are cutaway elevated perspective views of a sequence of theactuator mechanism and actuator release mechanism cycle for releasing adose of aerosol medication;

FIG. 11 is a side partial section view of the actuator release mechanismof FIG. 3;

FIG. 11A is a front elevated perspective view of the compound levertrigger mechanism of FIG. 11;

FIG. 12 is an elevated perspective side view of the trigger pin tip ofFIG. 11;

FIGS. 13A and 13B are respectively a side view of and an unwrapped viewof the rotary cam of FIG. 6;

FIG. 14A is a top plan view of the release ring of FIG. 6; FIG. 14B is aside view taken along line 14B--14B of FIG. 14A;

FIG. 15 is a top perspective view of the driver of FIG. 6;

FIGS. 16A, 16B and 16C are respectively side, top and bottom views ofone housing of the durable body of FIG. 1;

FIG. 16D is an enlarged view of the flow sensor surface of theembodiment of FIG. 1;

FIGS. 16E, 16F, and 16G are respectively side, top and bottom view ofthe other housing of the durable body of FIG. 1;

FIG. 16H is a front view of the chassis of FIG. 3;

FIG. 17A is top view taken along line 17A--17A of FIG. 3 of the airwaycover of FIG. 1;

FIG. 17B is a cross-sectional view taken along line 17B--17B of FIG.17A;

FIG. 17C is an end view taken across line 17C--17C of FIG. 17A;

FIG. 18A is a cross-sectional view of an asymmetric orifice meter foruse in the flow transducer of FIG. 1;

FIG. 18B is a cross-sectional and schematic view of the flow transducersurface of FIG. 1;

FIG. 18C is a rear view taken along line 18C--18C of FIG. 18B;

FIG. 19A is a flow chart of the operation of the actuator mechanism andthe actuator release mechanism of FIG. 1;

FIG. 19B is a flow chart of a process for delivering aerosol inaccordance with an embodiment of the preset invention; and

FIG. 20 is a plot of analog to digital converter counts versus time(data points) illustrating the corrected and uncorrected flow data inaccordance with offset drift correction of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Referring to FIGS. 1-4, an aerosol delivery device in accordance with apreferred embodiment of the present invention is shown. It includes adurable body 2 and a medication cassette 4, which interconnect toprovide a hand held aerosol device 6 in accordance with the presentinvention. Device 6 includes an outer body 10, a mouthpiece 20, acanister containing a reservoir of medication 30 to be dispensed, ahousing 40, an actuator mechanism 200, an actuator release mechanism300, control electronics 50, a battery 60, and a flow transducer system600.

Battery 60 is illustrated in FIG. 3 as two conventional AAA size 1.5volt batteries, which are inserted in suitable receptacles in durablebody 2, having an access cover panel 61. Alternate battery sources couldbe used, including rechargeable batteries. Battery 60 also may bereplaced or supplemented by an AC/DC convertor for operating device 6off conventional line current.

Referring to FIGS. 3-5, canister 30 includes a body 31 containing areservoir of medication to be released, a valve stem 32 for releasing anamount of the medication, and a bottom 34. Canister 30 is preferablyconstructed so that an amount of the stored medication is released whenvalve stem 32 is sufficiently pressed relative to body 31 (also referredto as "held down" or "depressed").

In the preferred embodiment, canister 30 and valve stem 32 are part of astandard metered dose canister such as can be used with conventionalmanually operated metered dose inhaler devices. In an alternateembodiment, canister 30 and valve stem 32 may be constructed as a simplevalve and reservoir body 31 which operates to release an aerosol for aslong as valve stem 32 is sufficiently depressed relative to body 31.Thus, the dose released by a straight valved canister can vary with thetime valve stem 32 is maintained depressed. Both canister constructionsinclude internal return springs (not shown) that return valve stem 32 tothe outer position which seals the reservoir closed to the atmosphere,when the actuating force is removed.

The reservoir in canister 30 may contain any selected medication (orother material to be delivered) in liquid, gas, or dry powder form.Where appropriate, a suitable propellant or carrier or an agitator forforming an aerosol of the liquid, gas or powder for delivery to thepatient also is provided.

Canister 30 is combined with mouthpiece 20 and housing 40 to formcassette 4. Cassette 4 is used to provide medication to durable body 2for automatic release in accordance with the present invention. Cassette4 also is constructed so that it can be used as a conventional manuallyactuated metered dose inhaler device, apart from the durable body 2.This is to allow the patient to obtain manual delivery of medication inthe event that durable body 2, or some component thereof, fails, e.g.,battery 60 is discharged. Cassette 4 is a replaceable component. It canbe inserted and withdrawn from durable body 2 by the user. Thus,cassette 4 can be made disposable and/or recyclable.

Housing 40 is constructed with an interior shape that corresponds to theshape of canister body 31, e.g., a cylindrical structure. Housing 40also is constructed with an outer shape that fits into a complimentaryshaped receptacle 520 in durable body 2. Housing 40 has a bottom end 45having an outer dimension that is larger than the outer dimension of thetop portion. The dimension of bottom portion 45 provides a bearing seat47 which contacts a ledge 447 built into a receptacle 520 of durablebody 2 for proper placement of cassette 4 (see FIGS. 16E, 16G). A pairof locking tabs 42 extend downwardly from bottom end 45. Tabs 42 areconfigured to interfit lockingly with a pair of corresponding apertures28 in mouthpiece 20 to secure canister 30 inside and between mouthpiece20 and housing 40.

Housing 40 has at its top end 46 an in-turned annular flange 48 which isdimensioned to hold canister 30 in place inside cassette 4 with valvestem 32 seated in valve stem receptacle 21, but not depressed relativeto body 31. This provides for securing the medication inside cassette 4so that the patient cannot remove easily the canister 30, or morepreferably cannot be non-destructably removed from the cassette. Annularflange 48 also is dimensioned to permit a person to depress canister 30manually, pressing body 31 relative to valve stem 32, to release a doseof medication. Most canisters 30 containing a blend of medication andpropellent under pressure have a concave bottom 34. Therefore, it isadvantageous to provide a disk 35 between flange 48 and canister bottom34. Disk 35 thus makes it easier to operate manually canister 30. Disk35 may be flat or convex and may be made of a rigid plastic or metal.

In an alternate embodiment, cassette 4 is made to be reusable withdifferent canisters 30, and flange 48 is omitted. In such case, africtional engagement of valve stem 32 and valve stem receptacle 21 willhold canister 30 inside housing 40. In yet another embodiment, cassette4 may be sealed at end 46 so that it cannot be manually actuated. Thisis useful where the medication to be delivered is a narcotic and is tobe dispensed only by the durable body under programmed control.

The top portion 46 of housing 40 also includes two notches (orapertures) 49. These are used by a driver element of actuating mechanism200 in connection with the automatic release of medication and isdescribed below.

Housing 40 also contains a multi-bit code which is representative of itscontents. In one embodiment, as illustrated in FIGS. 4 and 7-9, the codeis in the form of a series of protrusions 41 (or nubs) on its peripheryat a selected location. In order to insert fully and correctly cassette4 into body 2 to form an operable device 6, protrusions 41 must matewith a corresponding slotted disc or keyplate 440, which has previouslybeen secured to a chassis 400 inside durable body 2 (see FIG. 6). Thekeyed protrusions 41 and keyplate 440 thus may be used to provide formedication identification and a level of protection against insertingthe wrong or an unauthorized medication into body 2.

In one embodiment, there are a maximum of six protrusions 41 spaced toprovide physically a six bit codeword, based on the presence or absenceof a protrusion 41 at each location. Each durable body 2 may thus beprovided with a keyplate 440 that is constructed to receive onlycassettes 4 having one selected codeword matching keyplate 440. Thisconstruction provides for a dedicated durable body 2 which can only beused to deliver medication from a cassette having the one code, unlessthe keyplate 440 is changed.

In an alternative embodiment, multiple bit words represented byprotrusions 41, may be used to identify the pertinent deliverycharacteristics for a selected medication. Such information may includethe concentration and dosage delivery information,.how many dosages arein the canister 30 initially, the dosage frequency, time betweensuccessive dosages, when during the inspiration the dosage is to bereleased, the duration of the release of dosages or some combination ofthe foregoing. This may be achieved by assigning to each codeword adelivery protocol for the particular parameters to be used by controlelectronics to delivery medication. Thus, durable body 2 is adapted toread the multi-bit code provided by protrusions, e.g., by a series ofmicroswitches which are pressed closed by protrusions 41, look up in alibrary of stored delivery protocols the codeword read, and select fromthe library the corresponding delivery protocol which is loaded into thecontrol electronics 50 for administering the medication. In thisalternate embodiment, the medication identification also may be a partof the codeword. It is noted that more or less than six bits andcorresponding protrusions 41 could be used. Similarly, the codeword readcould be an identification code for the selected medication, which couldbe determined from a library along with the correct delivery parametersfor that medication.

In yet another alternative embodiment, instead of or in addition tophysical protrusions 41, an active or passive electronic circuit element41B (see FIGS. 4 and 9) is provided which provides code information to acorresponding decoder circuit in durable body 2 (not shown). Such anelectronic circuit could be an impedance value having a correspondingdelivery protocol and/or medication identification meaning, a digitalcodeword or, in an even more sophisticated version, a memory devicecontaining electronically readable data, e.g., a read only memory (ROM)device, programmable read only memory device (PROM), non-volatile randomaccess memory (RAM) or the like. Such a memory device may contain one ormore codewords that identifies the medication, the number of dosages ofmedication in canister 30, and optionally the delivery protocol(complete or pertinent parts) for that medication. In such case, durablebody 2 will have electrical contacts (not shown) for connecting to theelectric circuit 41B and obtaining the code and/or data containedtherein digitally, serially, in parallel, or as an analog signal value.

Further, the electronically readable code and/or data could identifyeach canister (or cassette) uniquely. This permits durable body 2 torecord a log of use for each individual canister 30 inserted andmaintain a running count of the number of dosages remaining in a givencanister 30 or the number of dosages delivered from that canister 30.This unique identification permits a patient to deliver more than onemedication using different medication cassettes 4 and the same durablebody 2. In this embodiment, durable body 2 contains correspondingsensing contacts (not shown) that mate with cassette 4, e.g., duringinsertion of cassette 4 into body 2, or whenever cassette 4 is placed inthe open position, to read the information represented by protrusions 41and/or any electronic circuit 41B. Optionally, the electrically readabledata could be downloaded into memory in control electronics 50, e.g.,during insertion, and off loaded back to the cassette, e.g., duringwithdrawal. This would obviate the need to always be connected to thecassette electrical circuit 41B. Different uniquely identified cassettes4 may be used in the same durable body 2, whereby control electronics 50can maintain separate counts of remaining dosages and/or delivereddosages for each cassette 4 by using the unique identification code asan address.

In yet another alternative, cassette 4 provided with memory 41Bcontaining programming information for use by durable body 2 may bereprogrammed by durable body 2 so as to maintain in memory 41B anaccurate count of the number of doses remaining and/or alreadydelivered, and other sensed parameters that are logged. This will permitusing the same cassette 4 in different durable bodies 2 without losingthe count or other logged information.

Referring again to FIG. 6, the larger protrusion 41A is used foraligning cassette 4 for insertion into body 2 in the first instance andfor retaining cassette 4 inside chassis 400 of durable body 2 exceptwhen protrusion 41A is aligned for insertion and removal. A verticalrecess 406 is provided in chassis 400 (or in receptacle 520) to guidecassette insertion and extraction so that protrusions 41 align withkeyplate 440. The alignment also is used so that actuator mechanism 200will seat easily in notches 49. In the preferred embodiment, referringto FIG. 3, the insertion/extraction position is when mouthpiece 20 is inthe open position for administering an amount of medication (asillustrated in FIG. 1) and a latch 39 is used to fit underneathprotrusion 41A to hold cassette 4 in receptacle 520, once it is fullyinserted. A spring 39A is used to bias latch 39 under protrusion 41A assoon as cassette 4 is seated. A button or slide (not shown) is used toretract pin 39 for extraction of cassette 4 from body 2.

An annular recess 405 is provided in chassis 400 (and/or receptacle 520)for receiving protrusion 41A whenever cassette 4 is fully inserted inbody 2 and in other than the insertion/extraction position (see FIG.16H). Annular recess 405 is used to prevent cassette 4 from falling outof durable body 2 inadvertently.

Bottom portion 45 of housing 40 includes an aperture 43 which cooperateswith mouthpiece 20 to form a flow path 24 through mouthpiece 20 and thebottom portion 45 of housing 40. When mouthpiece 20 is in the openposition, aperture 43 cooperates with airway cover 13 to provide flowcommunication through device 6 as discussed below. Housing 40 ispreferably made of a polypropylene material, which is preferably clear.This permits the user to read the product labeling provided by themanufacturer of the medication canister through the housing walls. Italso avoids the necessity to provide drug labeling on housing 40.Housing 40 is preferably recyclable.

Referring to FIG. 4, housing 40 also includes a location mark 44,preferably in the form of a surface indentation or protrusion, morepreferably an indentation located a selected distance from or on theaforementioned bearing seat 47 on housing 40. Location mark 44cooperates with a suitable contact switch 460, e.g., a Omron modelD2MQ-1 available from Digi-key, Thief River Falls, Minn., suitablypositioned in durable body 2. This contact switch provides a signal tocontrol electronics 50 indicating when cassette 4 is in the openposition for delivering medication.

Referring to FIGS. 3, 3A, 3B, and 3C, mouthpiece 20 is a tubular bodythat has a mouth end opening 23, a top end opening 29, a valve stop 21which incorporates a flow path 21A and a nozzle 22, a pair of apertures28, and provides a flow path 24 generally along an axis labeled Apassing through the center of mouth end 23 and nozzle 22. Nozzle 22 andits flow path 21A are conventional in design and directed to release anaerosol cloud along axis A. A preferred embodiment of nozzle 22 and flowpath 26 includes 0.018 inch (0.46 mm) diameter orifice for nozzle 22 anda 0.94 inch (23.88 mm) diameter for flow path 26.

Mouthpiece 20 is illustrated as having a symmetrically squashed ovaltube, with rounded sides and relatively flat top and bottom faces. Theinterior dimensions should be selected not to interfere adversely withthe dispersion pattern of an aerosol released at nozzle 22 during aninhalation. The outer dimensions are selected to be comfortable for apatient to engage with their lips with a reasonable air-tight seal.Mouthpiece 20 may be made of a polypropylene material.

Top end 29 of mouthpiece 20 opens to mate with bottom portion 45 ofhousing 40. The squashed oval section of mouthpiece 20 is contoured toblend into a rounded and curved inside or bowl-like back sectiongenerally illustrated as region 29A. Region 29A allows the flow to passbetween aperture 43 of housing 40 and mouth end 23 sufficiently smoothlyto entrain an aerosol generated by nozzle 22 during an inhalation. Italso permits flow in the other direction for measuring exhalation.Preferably, the mouthpiece flow axis A intersects with the back wall ofregion 29A near the interface of mouthpiece 23 and housing 40. Aperture43 is a substantially rectangular opening (when the curved wall isflattened) that is about as wide as the diameter of top end 29 and has aheight that in the curved shape has a chord about 75% of the height ofmouth end 23. Other dimensional relationships could be used.

As noted, apertures 28 provide for receiving housing tabs 42 andsecurely locking together housing 40 and mouthpiece 20. This is so thatthe patient cannot remove canister 30 from housing 40 withoutconsiderable effort. Locking tabs 42 and apertures 28 also cooperate totransfer force from a compression spring 210 to protrusion 41A andlocking pin 39, and to rotate cassette 4 in body 2, after insertion, byturning mouthpiece 20 about the axis B formed by valve stop 21 flow path21A, and canister 30. The locking tab aperture construction should beunderstood also to include having one or both of the locking tabsprojecting from the mouthpiece and fitting into a corresponding aperturein the housing.

In an alternative embodiment (not shown), in place of locking tabs 42and apertures 28, mouthpiece 20 and housing 40 could interfit in amanner that permits separation for replacing canister 30 inside andreusing housing 40 and/or mouthpiece 20 for a different canister 30 andfor cleaning mouthpiece 20 and nozzle 22. This may be obtained, e.g., bya threaded interconnection or a bayonet-type connection between housingbottom 45 and mouthpiece top and opening 29, provided that cassette 4can be rotated about axis B by the mouthpiece 20 without mouthpiece 20separating from housing 40. Care must be taken to be sure that the forcefrom compression spring 210 will not cause mouthpiece 20 to separatefrom housing 40 or change the axial distance between mouthpiece 20 andprotrusion 41A. Such a design is useful for adapting standard metereddose canisters for use in the present invention and permitting thepatient to obtain refills of the same medication from sources, e.g.,other than the source that supplied the cassette.

Referring now to FIGS. 3 and 6-15, actuator mechanism 200 and actuatorrelease mechanism 300 provide for electromechanically firing canister30, under control of control electronics 50, in response to the sensedinspiratory flow satisfying a provided flow delivery threshold. Thepredetermined flow delivery threshold may be a selected flow rate, aselected flow volume, or some combination of the two. In the preferredembodiment, the flow delivery threshold is a combination of the sensedflow rate being within a range defined by a selected minimum flow ratethreshold and a maximum flow rate threshold, and the flow volume beingwithin a range defined by a selected minimum volume threshold and amaximum volume threshold.

The delivery threshold is satisfied in the following manner. First, thesensed flow rate is checked. If the flow rate is in the correct rangebetween the upper and lower limits, the flow volume is checked. If theflow volume also is in the correct range between the upper and lowervolume limits, then the delivery threshold is satisfied and a deliverywill occur. Otherwise delivery is inhibited.

If delivery is inhibited for the entire inhalation, then the flow volumeand flow rate threshold parameters may be lowered recursively. In thisregard, during the inspiratory flow, the flow transducer system monitorsand stores the peak flow rate and the total inhaled volume. At the endof the inhalation, which is sensed by passing through a zero flow state,control electronics check to see if a delivery event occurred. If itdid, then the shot count of doses remaining and/or delivered is updatedand the system waits for the next inhalation (and delivery attempt).Control electronics also may include a timer to prevent too frequentdelivery of medication (overmedication).

If a delivery was not made, then the delivery threshold is checked. Morespecifically, the peak flow rate and inhaled volume values of the flowthat failed to cause a delivery are reduced by a selected percentage,e.g., 25%. The reduced values are compared to respective preselected(programmable) default values for the minimum flow rate and flow volumethresholds. If the percentage of the sensed peak flow rate for thefailed breath is less than the default minimum flow rate threshold, thenit is used as the minimum flow rate threshold for the subsequentdetected breath. Otherwise the default value is used. Similarly, if thepercentage of the sensed total volume for the failed breath is less thanthe default minimum flow volume value, it is used as the minimum flowvolume value for the subsequent breath. Otherwise the default value isused. If the subsequent breath also falls, then its sensed peak flowrate and inhaled volume are similarly processed in this recursivemanner, to select new delivery threshold suited to the patient'scondition at the time of delivery.

In one useful embodiment, the default values, each of which isprogrammable, are: upper flow rate 80 l/m, lower flow rate 40 l/m, upperflow volume 1.25 l, and lower flow volume 1.0 l. Although in thepreferred embodiment the upper limits are not recursively changed, in analternate embodiment they could be changed, e.g., as a selected multipleof either the lower thresholds or the sensed peak values. Other flowdelivery threshold parameters also may be used.

The actuator mechanism 200 includes a compression spring 210, a helicaltorsion spring 220, a rotary (helical) cam 230, and a driver 240. Eachof these elements is oriented in axial alignment with the longitudinalaxis B of canister 30. The actuator release mechanism 300 includes atrigger mechanism and a motor 321 for driving the trigger mechanism,which are located off of axis B.

Rotary cam 230, which is illustrated also in FIG. 13A, has a first camsurface 232 which cooperates with a pair of cam followers 430. Camfollowers 430 are attached to chassis 400 in durable body 2 on oppositesides of cam 230 in an appropriate location. Rotary cam 230 will thusrotate in one direction with cam surface 232 sliding against camfollowers 430 so that rotary cam 230 moves upwardly along axis B shownin FIG. 6 as it rotates. Rotary cam 230 has no effective lower camsurface. This allows cam 230 to move downwardly along axis B withoutrotating. Vertical motion is imparted by release of compression spring210. Rotary motion is imparted by release of torsion spring 220. Thedistance that cam 230 translates up and down corresponds to the distancevalve stem 32 must be depressed relative to canister body 31 to releasea metered dose of aerosol. For standard metered dose inhaler canisters30, the distance the valve stem must be depressed is on the order of 0.1inch (2.5 mm). Cam 230 may be made of any suitable material, such asDELRIN AF.

Referring to FIG. 13B, rotary cam 230 is illustrated in an unwrappedview illustrating the 0.333 inch (8.46 mm) pitch, a height of 0.227inches (5.77 mm), a distance D1 of 0.1 inch (2.5 mm) plus the thicknessof cam followers 430, and a helical face cam.

Rotary cam 230 is secured at its top to compression spring 210 and totorsion spring 220, as shown in FIG. 6. The other ends of springs 210and 220 are fixed, e.g., to chassis 400 or body 2. Rotary cam 230 issecured at its bottom to release ring 233, by a keyed interconnectionincluding key protrusion 239 (shown in face view of FIG. 13A) of cam 230and slot 235 of release ring 233. Cam 230 does not rotate relative torelease ring 233.

Referring now also to FIGS. 14A and 14B, release ring 233 is an annularring, having a radial groove (or recess) 236, a radial slot 234, and akeyway 235 for securing release ring 233 to cam 230. Release ring 233also may be surface treated to improve hardness, e.g., chrome plating.It is preferably a hardened tool steel ring (65-70 Rockwell C).

Referring now also to FIGS. 6-10, 11, 11A, and release ring 233 and itsradial groove 236 and radial slot 234 cooperate with the triggermechanism and motor 321 as follows. The trigger mechanism includes atrigger pin 312 with a generally rectangular cross sectional base 311and a multifaceted tip 313. As shown in FIG. 6, trigger pin 312 has afirst position where the top surface 343 of its tip 312 rests underneathrelease ring 233 in groove 236, with compression spring 210 incompression and torsion spring 220 in torsion. Compression spring 210biases release ring 233 downwardly with groove 236 receiving trigger pintip 313 securely seated inside. Torsion spring 220 biases release ring233 to rotate, but trigger tip 313 being inside groove 236 and/or slot234 prevents such rotation.

In accordance with the present invention, top surface 343 of trigger tip313, which is in contact with groove 236 on the bottom of release ring233, is cut at an angle α1 to the top surface 342 of base 311. Surface342 is essentially parallel to the plane of release ring 233.Consequently, the downward pressure exerted by compression spring 210acts on surface 343 to urge trigger pin 312 out from underneath releasering 233. However, trigger pin 312 is maintained in the first position,under release ring 233, by motor 321 (not shown in FIG. 6), in a mannerthat is described below.

Referring to FIG. 7, the trigger mechanism has a second position wheretrigger pin 312 is moved out from groove 236 and under release ring 233and is located in slot 234. Slot 234 and groove 236 are in radialalignment, with slot 234 being located in the outer perimeter of releasering 233. This is illustrated in FIG. 14B. This movement allows slot 234to move downwardly, straddling trigger pin 312, and as a resultdepresses canister 30. Torsion spring 220, however, biases release ring233 so that slot 234 presses against a side wall 341 of trigger tip 313.Consequently, torsion spring 200 remains in torsion.

Side wall 341 also is provided with an angle α3 relative to base wall311A (see FIG. 12B) which responds to the rotational pressure exerted bythe opposing inner wall of slot 234 to urge trigger tip 313 out of slot324. The result of this ejection, when it occurs, is that release ring233 (and rotary cam 230) will rotate as torsion spring 220 releases.However, motor 321 retains trigger pin 312 in its second position for aselected time period, so that cam 230 does not rotate (not shown in FIG.7), as will be described below. Side wall 341 also is cut at an angle α2relative to the wall of base 311 opposite to wall 311A to correspond torelease ring 233 to minimize or reduce energy lost from compressionspring 210 due to friction, thereby to maximize the energy transfer fromspring 210 to canister 30. The front end wall 311B may be cut at anangle suitable to provide clearance as tip 313 pivots, as describedbelow.

Slot 234 is configured with its walls cut at an angle α1 relative toaxis B as shown in FIG. 14B. Referring to FIG. 12 trigger pin tip 313top surface 343 is formed at an angle α1 relative to a plane horizontalto axis B, and trigger tip side surface 341 is provided with an angle ofα3, relative to a plane parallel to axis B. The angles α1, α2, α3 and β1are selected so that predetermined force magnitudes, which, if notcounteracted by motor 321 holding trigger pin 312 in position, wouldcause trigger pin 312 to be forced out from under ring 233 to releasecompression spring 210 to deliver medication, and then out from slot 234after the release of medication to release torsion spring 220 to recockcompression spring 210. Although the angles are a matter of designchoice, one suitable angle for each of α1, α2, α3 and β1 has been foundto be about 15 degrees.

Referring to FIGS. 3, 6-11, and 15, positioned between release ring 233and cassette 4 is driver 240. Driver 240 has a base 241 having a topsurface including a stepped drive dog 245, and a lower surface thatincludes two drive lugs 242 and two bottom surfaces 248, as illustratedin FIG. 15. Drive lugs 242 are respectively seated in notches 49 ofcassette 4 (housing 40) and bottom surfaces 248 are in contact with base34 of canister 30 (or disk 35, if one is used). The top of base 241 hasa top planar surface 243 over a first portion and a second planarsurface 244 over a second portion that is in a plane below top planarsurface 243. There are two step drive dogs 245 corresponding to thedifference in height between surfaces 243 and 244 as illustrated in FIG.15. One of the two steps 245 serves as a drive dog to rotate cam 230acting on cam protrusion/step 239 whenever cassette 4 is rotated to theclosed position. The other step 245 serves as a stop to preventoverrotating cassette 4 past the open position. The two steps thus limitcassette 4 to a rotation of about 180 degrees from open to closedpositions. The position for insertion and withdrawal is at the full openposition (180 degree position) relative to the closed position.Preferably, there are two drive lugs 242 and corresponding notches 49,although more than two of each could be used.

Driver 240 is used for cocking rotary cam 230. This occurs by rotatingcassette 4 about axis B to rotate driver 240. This causes one step drivedog 245 to engage and rotate cam 230. This in turn causes cam 230 andrelease ring 233 to rotate and place torsion spring 220 in torsion.Release ring 233 and cam 230 are then locked in place with torsionspring 220 in torsion, when they are rotated so that the top surface 343of trigger pin 313 engages groove 236. (See FIGS. 8-10.)

Driver 240 also is used for pressing canister body 31 downwardly,relative to valve stem 32 and cassette housing 40, to release an amountof aerosol. In this regard, the release of compression spring 210 movesrotary cam 230 and driver 240 axially downward (without rotation) alongaxis B. See FIG. 7, where drive lugs 242 are illustrated as fully seatedin housing slots 49.

Referring now to FIGS. 3, 11, and 11A, actuator release mechanism 300 isshown comprising motor 321 and the trigger mechanism. In the preferredembodiment, motor 321 includes a lead screw 322 that rotates only in asingle direction of rotation. Preferably, lead screw 322 has multi-startthreads, e.g., three or five starts. The trigger mechanism has a ratchetaction comprising a ratchet member 323 whose movement is controlled bylead screw 322, a return spring 326, a main lever 314 and a secondarylever 315. Return spring 326 is used to return the ratchet member 323 toa starting position in the absence of an external force pressing ratchetmember 323 against return spring 326. Ratchet member 323 is configuredso as to catch on lead screw 322 so that an external force directedagainst return spring 326 causes ratchet member 323 to sit against athread of lead screw 322. As a result, as long as the external force isapplied, the position of ratchet element 323 can be controlled byrotating lead screw 322.

In one embodiment, the ratchet member 323 is a bent piece of springsteel about 0.002 inch (0.05 mm) thick having an upturned edge 324 thatis secured to a pusher plate 328 by, e.g. a plastic rivet 329. Rivet 329may have an aperture 330 for passing along lead screw 322. A guide bar325 is provided extending between a motor mount 450 and a portion ofchassis 400 and parallel to lead screw 322, over which return spring 326is passed. Guide bar 325 provides stability, minimizes binding, andprevents plate 328 from rotating. In this regard, plate 328 also has abushing 328A having an aperture 331 which receives guide rod 325 andthus travels along lead screw 322 and guide 325, with return spring 326between plate 328 and motor 321. Preferably, motor 321 is secured to amotor mount 450 so that spring 326 is between plate 328 and motor mount450.

Trigger pin 312 is preferably mounted in a compound lever having a mainlever 314, with trigger pin 312 protruding from one side of main lever314, a secondary lever 315 that is pivotally connected to main lever 314by rod 316, and a cut-out portion 317 in secondary lever 315. Main lever314 is secured to chassis 400 so that it pivots about an axis 318 at itsbottom end. Secondary lever 315 also is connected to chassis 400 aboutreaction pivot 319. Motor 321 may be, for example, part No. DNI2K51N1B,available from Canon, Inc. Importantly, motor 321 consumes very littlecurrent, on the order of 130 ma when the motor is running, which occursduring a 2.5 second operation, of which the motor is off for aprogrammable time period, e.g., one second, which is typical forreleasing a dose of medication and recocking actuator mechanism 200.This amount is surprisingly less than the energy consumed by a solenoidthat is used to depress canister 30.

Apertures 330 and 331 are preferably made in a low friction material,e.g., teflon, or an acetal resin such as DELRIN. Aperture 331 isconfigured for passing therethrough guide rod 325, such that returnspring 326 is fixed between plate 328 and motor mount 450.

Motor 321 and lead screw 322 are mounted in alignment with secondarylever 315 so that lead screw 322 passes through cut-out portion 317 oflever 315. Return spring 326 biases spring metal 323 outwardly, i.e.,away from motor 321, and presses plate 328 against secondary lever 315.Lever 315 is in turn biased against plate 328 by the forces exerted ontrigger pin 312 by springs 210 and 220. The latter forces, when theyexist, are greater than the force of return spring 326. As a result,trigger pin 312, through levers 314 and 315, presses plate 328 towardmotor 321 so that upturned end 324 is pressed against and captured in athread of lead screw 322. Thus, as motor 321 is rotated, the threads oflead screw 322 will allow upturned end 324 of spring metal piece 324 tomove toward motor 321, under the pressing forces exerted by levers 314and 315. This in turn allows trigger pin 312 to be controllably forcedout from under release ring 233.

When trigger pin 312 is forced out from under release ring 233, out ofgroove 236 and slot 234, torsion spring 220 will release and cam 230will rotate. As a result, cam 230 will ride up on cam followers 430 toits uppermost position. As a result of this, the forces pressing ontrigger pin 312, which had been biasing upturned end 234 against releasespring 236 and the threads of lead screw 322, are removed. Accordingly,return spring 326 releases and pushes plate 328 outwardly, pressing onlevers 314 and 315 and trigger pin 312. This causes trigger pin 312 tobe rotated into position underneath release ring 233. In this regard, itis noted that the position of cam followers 430 on cam surface 232raises cam 230 high enough so that return spring 326 can urge triggerpin 312 in place underneath release ring 233. Lead screw 322 preferablyhas 12 turns per inch and 3 start threads.

To reduce the motor power requirement for the battery operated device,and hence extend the useful life, the helix angle of lead screw 322 isconfigured to approach, but not exceed, the friction angle between edge324 and screw 322. This ordinarily requires a relatively large pitch,e.g., 12 turns per inch on a 0.138 inch (3.5 mm) outer diameter leadscrew 322. In as much as there is no control of the rotational positionof lead screw 322 when it stops, the return of edge 324 would beimprecise. It was discovered that, to increase the accuracy of thelatching position where edge 324 engages a thread of screw 322, amulti-start thread, specifically a three start thread is employed. Thus,where a single start had a distance of 0.088 inch between adjacentthreads, a three start thread has a distance of 0.027 inch betweenadjacent threads. This is because the three start thread is thesuperposition of three one start threads each offset equally, along thescrew length. This provides for improved positioning resolution withouteither monitoring the rotational position of screw 322, rotating screw322, or using additional position sensing contact switches. Use of afive start thread provides improved position control.

Guide 325 and lead screw 322 provide for maintaining plate 328 andspring metal 323 properly oriented so that upturned edge 324 will againcatch in one of the threads of lead screw 322 on the next advance event.In this manner, motor 321 operates only in one direction of rotation andprimarily operates only as a brake to restrain plate 328 and secondarylever 315 and trigger pin 313 from withdrawing. By maintaining triggerpin 312 in place when motor 321 is stopped and not consumingelectricity, motor 321 efficiently controls movement of trigger pin 312to release a dose of aerosol medication. In contrast to prior artdevices, the electrically operated motor does not provide the actuationforce driving the motion of canister 30 to release the aerosol.

Upturned edge 324 is preferably bent with a curved edge, rather than astraight bend, so that it bows and is easily captured by the verticalwall of the threads of lead screw 322. Thus, upturned end 324 will beurged into a thread of lead screw 322 by lever 315, and will be passedso that it rides up and over the angled flights of the thread insuccession by return spring 326 (until trigger pin 312 is placed underrelease ring 233 and forced back by spring 210).

Having described the apparatus components, the method of operation ofthe actuator mechanism 200 and actuator release mechanism 300 will nowbe reviewed. Starting with FIG. 6, the apparatus is in the ready-to-fireposition with mouthpiece 20 already rotated by the user into the openposition. Compression spring 210 is maintained in compression betweenchassis 400 and rotary cam 230. Torsion spring 220 is maintained intorsion between chassis 400 and rotary cam 230. Trigger pin 312 ispositioned underneath release ring 233 and is seated in groove 236 withspring metal edge 324 engaged with lead screw 322 and return spring 326in light compression. Driver 240 is positioned with bottom surfaces 248flush against disk 35 which is flush against bottom 34 of canister 30,without depressing valve stem 32, and drive lugs 242 are partiallyinserted in notches 49. Protrusion 41A is positioned in annular recess405 in the open position and locked in position by latch 39 so thatcassette 4 will not fall out of chassis 400, receptacle 520, and body 2.The action of rotating cassette 4 to the open position places locationmark 44 in a position that is sensed by contact switch 460 secured tochassis 400. This actuation is sensed by control electronics 50 and usedto power up the electronics of device 6. A second microswitch (notshown) also is used to determine whether or not a cassette 4 is insertedin receptacle 520.

To release a dose, control electronics 50 monitor the user's inspiratoryflow, as described elsewhere, and determine when a provided deliverythreshold is satisfied. When this occurs, motor 321 is actuated torotate lead screw 322 to allow plate 328 to retract to a first stageposition. This is shown in FIG. 7. The position may be controlled byrotating lead screw 322 a selected number of revolutions or preferablyby using a contact switch 327 which is positioned to be contacted byplate 328 and shut off motor 321 in response to such contact. The latteris easier to implement.

During this movement, plate 328 moves away from canister 30 a firstdistance (as levers 314 and 315 pivot in response to the pressureexerted on trigger pin 312 by release ring 232). The first distance isselected so that tip 313 of trigger pin 312 slides out from groove 236under release ring 233 and into ring slot 234. When this occurs, cam 230is no longer supported by trigger pin 312 and is translated downwardlyby releasing compression spring 210. Accordingly, drive surfaces 246also are pressed downwardly and press canister body 31 relative to valvestem 32 to release a dose of aerosol medication. However, cam 230 isprevented from rotating under the force of torsion spring 220, which isstill in torsion, because trigger pin 312 is held in slot 234. Torsionspring 220 does, however, exert a force to bias release ring 233 slot234 against trigger pin 312 and maintain spring metal 323 edge 324pressed against the vertical thread wall of lead screw 322.

At the time motor 321 is stopped with trigger pin 312 in the first stagelocation, i.e., engaged in release ring slot 234 with canister 30 valvestem 32 fully depressed relative to canister body 31, controlelectronics 50 starts a timer. The timer controls how long motor 321,and hence trigger pin 312, is maintained in the first stage position.The time period is selected to be long enough to be sure that thedesired dose of aerosol is released from canister 30 in its selectedform, namely, dry powder, liquid or gas aerosol through the nozzle 22.

At the end of the selected time period, which may be controlled by atimer (more preferably a programmable value in a microprocessorcontrolled device), motor 321 is again advanced to allow plate 328 toreact further under the force exerted by ring slot 234. This allowslever 314 and lever 315 to rotate further and trigger pin 312 to beurged out of slot 234 because of the opposing angled faces of triggerpin 312, side face 341 and slot 234. This is shown in FIG. 8. Thefurther advance of the motor may be limited by another contact switch orby a set time period corresponding to a given number of rotations and,hence, distance of travel of member 324 along lead screw 322.

When trigger pin 312 slides out of slot 234, torsion spring 220 releases(in this case it unwinds). Because torsion spring 220 produces moreforce than compression spring 210, release of torsion spring 220 causesrotary cam 230 to rotate. As rotary cam 230 rotates, its upper camsurface 232 runs against stationary cam followers 430 and raises cam 230upwardly. As rotary cam 230 moves upwardly, it compresses compressionspring 210. Rotation and upward movement of cam 230 also results inreleasing valve stem 32 so that canister 30 is closed to the atmosphere.

In the preferred embodiment, wherein canister 30 is a metered dosecanister, this release action places canister 30 with its metered dosechamber in fluid communication with the reservoir of medication andcarrier or aerosol precursor material and refills the metering chamber.The refilling occurs relatively shortly after the dose was deliveredand, consequently, additional agitation of the medication and carrier oraerosol precursor prior to refill is not required. Thus, cam 230 comesto rest in its uppermost position, with cam followers 430 at one end ofcam surface 232, torsion spring 220 released, compression spring 210compressed, and metered dose canister 30 with a filled metering chamberand ready for delivering the next dose.

Advantageously, in the present invention, the helical torsion spring 220is used to recock compression spring 210, by transferring its energythereto without requiring the user to perform any operation. It shouldbe understood that a more complex spring could be used in place ofcompression spring 210 and torsion spring 220, so that release oftrigger pin 312 will transfer the energy that had been stored by a priorrotating cocking event to be stored in the axial compression component,for later use in depressing canister 30 for releasing the next dose. Italso should be understood that the direction of rotation about axis Bfor the various operations described herein maybe clockwise orcounterclockwise, with appropriate mirror image parts and angles beingusable.

Referring now to FIG. 9, after trigger pin 312 slides out of slot 234,motor 321 continues to advance for a period of time, e.g., 0.5 to 2seconds, or for a number of revolutions, that is sufficient for cam 230to rotate upwardly on cam followers 430. In this regard, the uppermostposition of cam 230 is high enough so that when return spring 326releases, it drives plate 328 along guide rod 325 back to the initialready-to-fire position and returns trigger pin 312 to apre-ready-to-fire position positioned underneath release ring 233. Inthis condition, compression spring 210 is compressed, torsion spring 220is released, and rotary cam 230 is held in its uppermost position by camfollowers 430 over trigger pin 312.

The pre-ready-to-fire condition is followed by a cocking operation,which places device 6 in the ready-to-fire condition. With reference toFIG. 10, the cocking operation is performed by rotating cassette 4 intothe closed position. As a result, one of the drive dogs 245 of driver240 engages protrusion step 239 at the bottom of rotary cam 230 andcauses cam 230 to rotate. This rotates cam 230 relative to cam followers430. As a result, cam 230 will move downwardly on cam surface 232 as itrotates until it is supported by trigger pin 312 acting on the releasering 233. At that point, cam 230 will continue only to rotate untilgroove 236 of release ring 233 is again engaged with the top surface oftrigger pin 312 and places cam followers 430 at the other end of camsurface 232. The engagement occurs at less than about 10° from the fullyclosed position (0°). When the user releases cassette 4 after it isfully closed, torsion spring 220 will tend to release. This results inslot 234 acting on trigger tip 313, which also inhibits rotation. Thislocks torsion spring 220 in torsion. Thus, device 6 is ready to beopened for delivering aerosol medication.

Because mouthpiece 20 has a length of about 1.38 inches (35 mm) from thecenter of rotation (Axis B), the patient has sufficient leverage torotate cam 230 and place torsion spring 220 in torsion, with sufficientforce to drive cam 230 to compress spring 210 after the next delivery ofmedication. Preferably, compression spring 210 stores on the order of 8pounds (3.629 kg) which is sufficient to depress valve stem 32 whenspring 210 is released. Torsion spring 220 preferably stores on theorder of 0.9 pounds-inches (1.0 kg-cm) which is sufficient to compresscompression spring 210 after the release of a dose of medication.

It will be appreciated that the present invention also can be practicedby variations of the mechanical structure described above. For oneexample, it is possible to use a release ring 233 which does not have agroove 233. In such an embodiment, trigger pin 312 is used to engageslot 234 to prevent torsion spring 220 from releasing and to restunderneath release ring 233 to prevent compression spring 210 fromreleasing. The advantage of this structure is that the distance oftravel of cam 230 along axis B for depressing canister 30 and forreinserting trigger 312 under release ring 233 is increased by the depthof groove 233, e.g., 0.015 inches. In such an embodiment, the angularconfiguration of trigger tip 313 may be modified if necessary, toprovide the required clearance as well as the restraining and ejectionfunctions.

For another example, it is possible to replace compression type releasespring 326 with a helical torsion spring that is mounted about pivot 318and to provide pusher plate 328 with a flange that hooks onto secondarylever 315 (not shown). In this embodiment, the torsion spring is used toact on primary lever 314, which in turn will pull secondary lever andplate 328 towards canister 30 for resetting trigger pin 312 underrelease ring 233 when the forces pressing plate 328 towards motor 321are removed. Yet another variation could use a torsion spring securedabout secondary lever 315 pivot 316.

The use of a compound lever 314, 315 minimizes the force requirements ofmotor 321, spring member 323, and return spring 326. This is importantin reducing the energy consumption requirements for a battery poweredhand held device. Indeed, the consumption requirements are reducedfurther by operating the motor as a controlled brake resisting theforces exerted by springs 210 and 220 and turning the motor off to actas a passive brake, except when a controlled retraction of trigger pin312 is to occur. During the time motor 321 is stopped in the first stageposition, it does not consume energy. Advantageously, motor 321 can rundirectly off battery 60, which simplifies the power supply circuitry andminimizes the bulk of device 6.

Another advantage of the present invention is that it provides openingmouthpiece 20 as a passive event, whereby it requires little effort. Italso obviates the need for the patient to have to cock the deviceimmediately prior to use. This can be important to patients who are indistress or suffering a severe asthma attack and who might in panicforget or be unable to cock a device.

The time that motor 321 is maintained in the first stage, with valvestem 32 depressed relative to canister body 31, can be selected andcontrolled by control electronics 50. Accordingly, the present inventionis particularly useful with canisters, valve stem receptacle flow paths,and/or nozzles that have relatively slow or long release times, i.e.,the time that the valve stem must be depressed to maintain open themetering chamber (for a metered dose inhaler) or a straight valvecanister to release the proper dosage of aerosol medication. In thisregard, most available metered dose inhalers have a release time on theorder of 90-100 msec, such that the valve stem must be held down forabout one-tenth second to ensure complete release. This is easy for mostindividuals to achieve. Slow release valves may have a greater releasetime, e.g., on the order of one-quarter second, three-quarter seconds,two seconds, or more. The release time of this length is more difficultto achieve manually on a reliable basis.

Advantageously, the present invention is able to deliver medicationsformulated to have long release times which heretofore could not be usedin a metered dose inhaler because of the difficulty of providing therequired release time. This feature also is particularly useful withstraight valve canisters and dry powder delivery systems where therelease time controls the amount of medication released.

Referring to FIGS. 1-3, 16A-H and 17A-C, durable body 2 may be formed ofa left half 11, a right half 12, and an airway cover 13, which provide aportable, hand held device. Body 2 also includes a display 510,preferably mounted in one of housings 11 and 12. Enclosed insidehousings 11 and 12 are one or more batteries 60, actuator mechanism 200,actuator release mechanism 300, chassis 400, control electronics 50, areceptacle 520 for receiving cassettes, and flow transducer 600.

Display 510 may be a liquid crystal display (LCD) device for displayingalphanumeric characters of measured flow or pulmonary functionparameters, or instructions to the patient for using device 6 undermicroprocessor control. The LCD display may display quantitative orqualitative measures. One such LCD display 510 is a custom part modelNo. 0219-3211-F14 available from DCI, Olathe, Kans. It provides fordisplay, in response to software programming, of one or more of shotcount of released (delivered) and/or remaining doses of medication, alow battery indication, a warning icon, e.g., "consult your doctor,"three arrows to indicate inadequate, nominal or acceptable pulmonaryfunction, annunciations for total exhaled volume, peak flow andannunciations indicating the day of week, time, month and year.

The display features of device 6 also may include a light emitting diode(LED) array 510' for indicating various parameters, for example, (1)that the device is on, (2) ranges of determined breath flows, e.g., goodflow corresponding to successful delivery, bad flow corresponding toaborted delivery, (3) a qualitative measure of a measured pulmonaryfunction, e.g., normal, nominal, and abnormal, and (4) relative changesin measured pulmonary function, e.g., improving the same degradingconditions. LED array 510' may include three LED devices, e.g., green,amber and red (or three of the same color), and appropriate labelingprinted on housing 11 or 12. A selector switch also may be provided toindicate which parameter is being displayed on array 510'.

Control electronics 50 preferably includes a microcontroller deviceincluding a microprocessor, RAM and ROM memory, and buffers, and alsoincludes external analog-to-digital converters, latches, RAM/ROM memory,and signal conditioning circuits for receiving and transmitting signalsin and out of control electronics 50, in digital and/or analog form.Such devices include a model 68HC11D3 microcontroller available fromMotorola, analog to digital converter part No. AD7701 available fromAnalog Devices, and interface amplifier model No. AD22050 available fromAnalog Devices for conditioning the signal from the pressure transducerfor digitization.

The microcontroller, memory, and analog-to-digital converter must havesufficient capability and processing speed for processing the outputsignal produced by flow transducer 600, convert the output signal to theflow rate signal and, in accordance with selected protocols, derive aflow value signal from the sensed flow rate for causing actuator releasemechanism 300 to release a dose of aerosol during inspiration of thepatient and determine pulmonary functions based on the acquired flowsignals. A suitable sampling rate is greater than 60 Hz, e.g., 75 Hz,for analog to digital conversion and processing.

Chassis 400 is secured to one or both of housings 11 and 12 such that itis adjacent an interior receptacle 520 for receiving cassette 4. Mountedto chassis 400 are cam followers 430, keyplate 440 for receiving onlycassette 4 having protrusions 41 that correspond to the plurality ofslots cut in keyplate 440, motor mount 450 for mounting actuator releasemechanism 300, annular recess 405 and contact switch 460 for sensing thepresence of location mark 44 on cassette 4 indicating that cassette 4 isfully rotated to the open position. Chassis 400 is securely mounted tobody 2. Receptacle 520 includes a first section that receives the upperpart of housing 40 and a second section that receives the lower part 45of housing 40. A ledge 447 separates the upper and lower receptaclesections and receives bearing surface 47 of cassette 4. Contact switch462 is used to indicate that cassette 4 has been inserted in thereceptacle adjacent to chassis 400.

Referring to FIGS. 16A through 16H one suitable form of the durable body2, excluding airway cover 13, is shown. With reference to FIG. 16E,housing 11 is shown with receptacle 520 for receiving cassette 4 havingannular recess 405 and keyplate 440 is shown. This embodiment includestwo batteries 60 and LCD display 510 and LED array 510' within housings11 and 12.

With reference to FIGS. 16B, 16C, 16E, and 16F, body 2 is provided witha contour that is easy for the patient to hold securely. The larger sideplanar walls of housing 11 and 12 are each angled at an angle of about4.5°. It should be understood that alternate configurations of housings11 and 12 could be used.

Referring to FIGS. 3 and 17A-17C, airway cover 13 connects to the bottomof body 2, more specifically, housings 11 and 12, after they have beensecured together. Airway cover 13 includes ports 507 at the larger enddistal to the patient's airway, and has a curved edge 501 in ahorizontal plane at the proximal end, adapted to receive the perimeterof region 29A of top end opening 29 of mouthpiece 20. This allowsmouthpiece 20 to rotate and maintain a close fit with the airway betweenairway cover 13 and the bottom of housings 11 and 12. In addition,airway cover 13 is provided with a corner surface bend indicated by 509,which receives the mouth end 25 of mouthpiece 20 when cassette 4 isrotated to the closed position. This provides a neat outer appearanceand a relatively smooth surface for durable body 2, which makes itsconvenient to carry in a pocket or pocketbook. It also provides aconvenient mechanism for blocking the open end 23 of the airway so thatmaterial is not lodged in the flow path. It also eliminates the need fora separate cap to cover the opening. The distance between the flat wallsection designated 508 of airway cover 15 and the bottom of housings 11and 12, designated as wall 506, is on the order of 0.38 inches (9.65 mm)and a width of 0.90 inch (22.86 mm) at the maximum dimensions. The sidewalls taper at nine degrees, 41/2° per side, to follow the outside ofhousing 11 and 12. Although these dimensions are not critical, they mustbe sufficiently large to provide for a flow path between mouth end 25 ofmouthpiece 20 and apertures 507 of airway cover 13 when mouthpiece 20 isrotated in the open position and provide a detectable pressuredifference between pressure tap 516 and atmospheric pressure whilemaintaining an acceptable air flow.

Referring to FIGS. 3, 16D, 18B and 18C, flow transducer system 600includes a pressure transducer 505, a durable flow measurement sectionhaving a contoured surface built into wall 506 at the bottom of housings11 and 12, airway cover 13, and a pressure port 516. Preferably, thecontour of wall 506 is flat in the cross section end view as shown inFIG. 18C. Airway 601 mates with the airflow path 24 (through mouthpiece20 end 23 and top end opening 29 the lower portion of 45 of housing 40,and out aperture 43). Airway 601 comprises the bottom wall 506, made ofthe mated housings 11 and 12, and airway cover 13.

In operation of the present invention, as the patient inhales or exhalesthrough the device, flow through path 601 is sensed at pressure tap 516in wall 506 and at atmospheric pressure (not shown) by pressuretransducer 505. The output signal of transducer 505 is converted to adigital value by control electronics 50 at a selected sampling rate andintegrated at that sampling rate to obtain inhaled or exhaled volume.Drug dispensation timing and therapeutic decisions are based upon thesemeasurements of flow rate and volume.

Airway cover 13 is removable to facilitate cleaning of the durable flowmeasurement section. It has a rectilinear wall section 508 which definesa cross sectional area with opposing wall 506. Wall section 508 has acorner 509 which opens out at almost a 90° angle to provide a largerdimensioned chamber 550. The distal end of chamber 550 has apertures(ports) 507 for air flow therethrough without any significant pressuredrop across apertures 507. The type of opening is not critical as longas chamber 550 allows the flow into the chamber to expand. Hence, a 90°bend is convenient, but not required.

Wall 506 has at the proximal end a tapered lead-in section whichincludes a ramp indicated by reference 511. Ramp 511 reduces thecross-sectional area between walls 506 and 508 at the beginning of ramp511 (indicated by reference 513) to a minimum cross sectional area atorifice throat 515. Wall 506 includes an undercut portion 512 underthroat 515, which connects throat 515 to a wall segment 519, is in thesame plane as wall 506 proximal to ramp 511 and provides about the samecross sectional area as at the beginning of the ramp 511.

Walls 506 and 508 are thus constructed to form an asymmetrical structurethat comprises elements of a pneumatic diode, a fixed orifice flowmeter, and venturi port flow meter. A pneumatic diode is a structurethat presents one flow resistance as the air passes in one directionacross the surface and a different flow resistance as the air flowpasses in the reverse direction. A fixed orifice meter is one thatpresents an orifice in the path that is generally symmetrical with theairflow path, but of smaller dimension. Flow through the orifice createsa differential pressure across the orifice which can be measured bysensing the pressure on either side of the orifice in a conventionalmanner. It is noted that the sides of airway cover 13 could be madestraight, rather than tapered. If so, then the cross sectional areabetween throat 515 and wall 508 must be accordingly adjusted to providethe same orifice area as when the side walls are tapered.

The orifice meter principle is simple. In order to generate a flowthrough an orifice there must be a pressure difference across theorifice. If there is no pressure difference then there will be no flow.Likewise, if there is a flow across an orifice, there will be a pressuredifferential that can be measured. The flow rate, Q, is dependent on astring of constants, the square root of the inverse of the air densityand the square root of the difference in pressure across the orifice.##EQU1## The terms K and A are constants dependent on the systemgeometry and g_(c) is a dimensional constant. In the present invention,only the pressure on the patient side of the orifice and the atmosphericpressure are measured.

The flow rate vs pressure drop curve is parabolic. Therefore, it wouldrequire a huge dynamic signal range to detect the small pressuresgenerated at near zero flows and also not peg the system signal duringhigh flow rates. The low flow rate sensitivity in one direction isrequired to measure accurately inhale maneuvers, which typically rangefrom 0-200 liters per minute. The large flow rate range in the otherdirection is required to measure the high flow rates during, e.g., aforced exhale maneuver which typically range from 0-800, more preferably0-720, liters per minute. The latter are used to measure a pulmonaryfunction.

It has been discovered that, by using an asymmetric orifice, instead ofthe usual symmetric orifice, such different ranges of flow rates can beeffectively measured by the same flow transducer over a relatively fullscale for maximum signal resolution in the different ranges.

When the device is in inhale mode, the flow is developed by reducedpressure at the patient side, drawing air over undercut 512 of wall 506.In this mode, wall 506 behaves essentially like an orifice meter, exceptthat there is a back eddy created by undercut 512. The back eddy helpsincrease the flow resistance in the inhale direction, thus adding to thetotal differential pressure.

On exhale, there is a different effect. The flow encounters a smoothtransition along ramp 511 to the orifice throat 515, which requires acertain amount of pressure to push it through. The pressure required isabout 40% as much as for the same inhaled flow rate. The pressuresensed, however, depends on the position of pressure tap 516 in wall506. If pressure tap 516 is placed at location 518 as illustrated inFIG. 18A, then the difference between exhaled and inhaled sensedpressures (for same flow rate) is about 2:5. If pressure tap 516 isplaced on ramp 511 as illustrated at 518' in FIG. 18A, then there isadditionally a venturi effect that comes into play. In this regard, asthe flow rate increases, there also is a pressure drop that issuperimposed upon the pressure required to generate the flow. Theventuri effect is also parabolic with respect to flow rate. The relativeposition of pressure tap 516 on ramp 511 determines the magnitude of theventuri effect. This allows for varying the difference between theexhaled and inhaled sensed pressures ranges from between 2:5 and 1:100or more, based on careful selection of the location of pressure tap 516on ramp 511. The venturi effect can be made strong enough so that sensedpressure can go negative with respect to atmospheric pressure at exhaledflow rates by placing pressure tap 516 very near the orifice throat 515.

As a result, wall 506 of the present invention yields a structure wheresensed pressure resulting from a flow in one direction can be radicallydifferent from sensed pressure from the same magnitude flow in the otherdirection. The inhaled flow rate vs. pressure drop curve depends mostlyon the selected size of the orifice, i.e., the distance between throat515 and wall 508, and somewhat on the shape of undercut 512. It alsodepends on pressure tap 516 position on ramp 511. The exhale curve alsodepends on orifice size, but is radically changed by the position ofpressure tap 516 along ramp 511 relative to the venturi throat 515. Thisallows for measuring flow rates in both directions using the full rangeof the transducer in each direction, even though the maximum flow rateshave different magnitudes.

Referring to FIGS. 3, 16D, and 18B, in one embodiment, the distancebetween throat 515 and wall 508 is 0.185 inches (4.69 mm). Thedimensions of undercut 512 is a radius of 0.067 inches (1.7 mm) having acenterpoint that is about 0.745 inches (18.9 mm) from backwall 517.Backwall 517 is part of the durable body 2 and interconnects with thebackwall of airway cover 13 that includes apertures 507. The thicknessof wall 506 at the throat 515 is approximately 0.161 inches (4.24 mm).Ramp 511 is comprised of two cylindrical segments having oppositecurvatures. The first curve begins tangential with wall 506 at end 513has a radius of about 0.732 inches (18.6 mm) from a centerpoint spaced0.6 inches (152.4 mm) from the orifice throat 515, perpendicular to wall506 and wall 508. The other curvature, which terminates as orificethroat 515, has a radius of about 0.791 inches (20.09 mm) having acenterpoint spaced 0.78 inches (19.8 mm) from throat 515 on the otherside of wall 506.

Pressure tap 516 is preferably a circular hole that extends through wall506 and terminates in ramp 511 facing wall 508. Pressure tap 516 ispreferably normal to the surface of wall 506 in which it terminates andspaced to one side or the other of the midplane as illustrated in FIG.18C. The precise location of pressure tap 516 is a matter of designchoice for the particular use of the device. Pressure tap 516 isconnected to transducer 505 by a flexible plastic tube 520, e.g., PVC.The PVC tube need not have the same diameter as tap 516. The diametershould not be so small as to wick moisture, e.g., 1/32 to 1/16 of aninch inner diameter. The orifice of pressure tap 516 will be about 0.030inches.

In the present invention, the pressure versus flow rate curve along flowpath 601 is typically non-linear in both directions. Applicants haverealized that it is impractical to design and construct a flow path 601with precise dimensions to obtain a flow having linear pressure vs flowrate characteristics.

A problem with using linear devices is that they are too bulky for ahandheld, portable device and typically contain screens or other orificearrays which become clogged or plugged during use and need to be cleanedor replaced to avoid inaccurate measurements. However, applicants alsohave realized that a linear relation is not required and can bedispensed with by calibrating the flow path 601, as actually built, toproduce from the actual sensed flow calibrated data. Moreover, byproviding flow transducer system 600 as part of durable body 2,applicants have realized that only flow path 601 needs to be calibrated,and not flow path 24. This further simplifies construction of mouthpiece20 and cassette 4, and avoids the need to maintain tight tolerancecontrols for the construction of those other parts. In this regard, themeasurement made is not the pressure drop through the entire system flowpaths 24 and 601, which might be changed slightly by minor variations incassette 4. Rather, the pressure drop measurement is obtained onlyacross the flow path 601 between housings 11 and 12 and airway cover 13,and hence is independent of minor variations in cassette 4. Further,total pressure drop through the entire system is also mostly independentof cassette 4 manufacture variations between the orifice 515 in the flowmeasurement section is substantially smaller and thus more restrictivethan the port 23 and mouthpiece 20 in cassette 4.

Accordingly, in accordance with the present invention, a calibrationlook-up table is derived and stored in nonvolatile memory of controlelectronics 50 for each body 2. This provides for measuring a flowdependent pressure signal, i.e., the voltage signal output fromtransducer 505 and looking up the corresponding calibrated flow value.In one embodiment, the look-up table is a selected number of data pointslong, e.g., 59 points. The look-up table may be considered as two arraysor, tables, each having 28 data points for flow in each direction andsharing the zero flow rate.

Control electronics 50 thus obtains the flow dependent signal, appliesthe obtained value to the look-up table, and performs piecewise linearinterpolation between the points in real time so that it can measurerapidly changing flow rates. The calculated flow values are thenintegrated to determine volume or used to measure a pulmonary function,as the case may be. The look-up table is generated during thecalibration of each device 6. Although in the preferred embodiment thevalid flow values, i.e., values above a selected noise threshold, arealways integrated, in an alternate embodiment, integration need notoccur unless a flow volume is required.

In a preferred embodiment, an automated calibration routine is used todetermine the look-up table.

First, the uncalibrated durable body 2 is placed on a fixture thatterminates in a dummy disposable cassette 4, the same way that apatient's drug cassette 4 would be inserted into the device. Second, aknown air flow is introduced through the durable flow path 601 by acalibrated flow controller. Third, the flow rate and transducer 505response to a known flow are recorded by a computer (not shown).Further, the flow rate is adjusted to the next flow level by the flowcontroller, and the second and third steps 2 are repeated for, e.g., upto 59 different flow rates in the two flow directions. Fifth, therecorded data is transformed into a calibration table and may be runthrough a curve fitting routine to look for outlying or bad data points.Those points, if any, are remeasured. Alternately, a curve fittingroutine may be used to find the best fit through the data prints to adesired degree of accuracy, e.g., 2nd order. Sixth, a calibration tableis then generated and downloaded into the RAM memory of controlelectronics 50. The table may be the raw data or curve fit data points.The calibration is then spot checked at several flow levels to assureproper loading of the table. A check sum is also stored in memory withthe calibration table so that the look-up table can be checked forcorruption each time the device 2 is turned on.

A preferred flow sensing transducer 505 used to measure these pressurechanges is a resistive strain-gauge type device having two ports. Oneport is vented to ambient pressure. The other port is connected by tube520 to the pressure tap 516 which is located within airway 601,preferably on ramp 511 (see FIG. 18c). Pressure changes at the airwayport 516 cause the resistances within sensor 505 to change. Theseresistance changes are provided in the form of a variable voltage outputwhich is digitized by control electronics 50. The digital value isconverted to a corresponding flow value using the predeterminedcalibration look-up table stored in the system memory PROM, ROM, ornonvolatile RAM. One suitable transducer 505 is model NPH-8-002.5DH,available from Lucas Novasensor, Fremont, Calif.

Pressure sensors 505 of this type are known to suffer from severalproblems. First, the devices exhibit thermal and long-term drift,causing the output signal to wander slightly after power-up. The outputsignal also varies with the orientation of the sensor. Normally, theseeffects would be negligible. However, in the application of the presentinvention, the parabolic nature of the flow-pressure curve makes theaccuracy of look-up table conversion very sensitive to these offsetchanges. This is because, at low flow rates, a very small change in thepressure signal maps into a relatively large change in the calculatedflow rate.

For example, it was discovered that if the offset of the pressure signalwas only measured at power-up and if the orientation of the transducerchanged or if device 6 was left on for more than a few minutes,erroneous flow rates of up to ±30 liters/minute would often be reported.Accordingly, it was realized that the offset would have to be monitoredand accounted for. The simple approach is to linearize the flow-pressurecurve (either mechanically or electronically) to eliminate this problem.However, as already noted, this effort proved to be unfeasible andunnecessary.

As realized by the inventors, because the sensitivity of the system tochanges in the offset of the pressure transducer cannot be easilyreduced to an acceptable level, the magnitude of the offset changes mustsomehow be lessened. Specifying tight tolerances for drift andorientation sensitivity would make transducer 505, or controlelectronics 50, prohibitively expensive. The inventors realized,however, that a cost effective solution is to measure and correct foroffset changes as they occur in real time. The inventors also realizedthat it is important to correct for zero-flow offset changes duringzero-flow conditions and that this presented a different problem ofdetermining when zero flow conditions occur even in the face of driftoffset.

The inventors discovered that the inherent noise of the unfiltereddigitized signal during a zero-flow state is about ±2 A/D counts. Theinventors discovered that even at low flow rates, when the sensitivityto flow variations is low, maintaining an airway flow rate whichproduces a pressure signal constant to within ±2 A/D counts for anylength of time is virtually impossible. Therefore, they realized, apressure signal remaining constant for a relatively long period of timeis indicative of a zero-flow state. This criterion was accordinglyselected and used to determine appropriate times to measure and modifythe zero-flow offset value.

The method assumes that any drift occurs slowly enough not to influencethe peak-to-peak variance calculated over the specified time period, andthat orientation changes are transient events.

According to a preferred embodiment of offset correction, the devicemaintains a buffer holding the last 25 A/D values, which corresponds to1/3 of a second of pressure data. The A/D values are the digitizedoutput of pressure sensor 505. After a new data point is placed in thisbuffer, the difference between the minimum and maximum values in thebuffer is calculated. If the calculated difference is less than or equalto three, then the system concludes that a zero-flow condition exists,and a new offset is calculated.

To calculate the new offset, the mean value of the 25 values stored inthe buffer is first calculated. The difference between this calculatedaverage, representing the current zero-flow reading, and the base valuefor this zero-flow signal is calculated. This difference is then storedas a new A/D offset term. If each direction of flow is to have asymmetrical range of A/D counts, then, the base zero flow condition isthe midpoint of the A/D range, e.g., zero for a bipolar A/D converter,or 32768 for a 16-bit unipolar A/D converter.

The offset drift correction aspect of the present invention will bebetter understood by the following example. On power-up initialization,the system measures an average zero-flow pressure signal of 30000 A/Dcounts. The range of the unipolar A/D converter is 0-65535 counts,corresponding to an input range of 2.5 volts, such that each A/D countis 38 μV. For a symmetrical A/D count sample, the ideal base zero-flowsignal is thus: ##EQU2## The A/D offset term is then calculated to be:

    30000-32768=-2678 counts.

The offset term is subtracted from all subsequent A/D measurementsbefore these readings are mapped into flow values using the look-uptable.

After some operating time, the pressure transducer output driftsslightly, resulting in an unadjusted average output of 31000 counts forthe current zero-flow condition. When the original calculated offset of-2678 counts is subtracted from this value, an adjusted average of 33768counts is obtained, which would normally cause a large erroneous flow tobe reported. However, the peak-to-peak variance over the previous 25values will eventually become less than 4 A/D counts. At this point thesystem will assume a zero-flow state exists and computes a new offsetterm to be:

    31000-32768=-1678 counts.

A subsequent unadjusted pressure reading of 31000 counts will now resultin an adjusted value of:

    31000-(-1678)=32768 counts.

Note that the new offset now compensates for the 1000 count drift in thepressure signal.

The parameters specified above have been implemented in a prototypedevice, and appear to work well in allowing the system to quicklycompensate for offset drift and orientation changes. See FIG. 20, whichis a representative plot showing in the lower curve the actual offsetdrift of the flow sensor over time (in number of data points, where thetime interval between data points is 13.3 ms) and in the upper curve thecorrected value according to the offset correction routing of thepresent invention. It is noted that many other combinations of filterlength and peak to peak difference may work equally well. Nonsymmetrical ranges of A/D counts also could be used if it is desired tohave either greater resolution or a greater flow range in one of the twodirections. This approach also could be performed using hardwarecircuits as well as software controlled microprocessor signalprocessing.

Referring to FIG. 19A, a block diagram illustrating the interaction ofcontrol electronics 50, actuator release mechanism 300, actuatormechanism 200, and position sensor 460, e.g., a contact switch, areshown. A flow diagram showing the essentials of a process forcontrolling the release of a dose of aerosol medication is shown in FIG.19B. One suitable routine is as follows. When mouthpiece 20 is rotatedinto the open position, position sensor 460 senses location mark 44 andinitializes the control electronics at step 801. Step 801 is followed byprocessing flow data, including digitizing the output signal provided bytransducer 505, passing the digitized data into a buffer storage memory,mapping the acquired pressure data using the look-up table intodetermined flow rates, and determining current calibrated flow rateinformation at step 802.

At step 803, the system determines whether or not the time for releasinga dose has occurred. In this regard, the flow rate is checked todetermine if it is an inhalation. If it is, the acquired flow data iscompared to preselected delivery threshold parameters. For example, aspreviously described in detail, the flow rate is checked first todetermine if it is within a flow rate range. If it is, then the flowvolume information is checked to see if it is in a flow volume range. Ifboth ranges and satisfied simultaneously, then, at step 804, motor 321is turned on, a "firing" flag is set, a "motor1" flag is set, and a twosecond alarm is set. This results in the lead screw 322 rotating so thatratchet member 323 moves toward motor 321 as trigger pin 312 is urgedout from under release ring 233 and into slot 234, and the processingreturning to step 802 to process new data. If it is not time to fire,then the routine queries whether the "firing" flag is set at step 805.If the "firing" flag is not set, the routine returns to processadditional new data at step 802. If the "firing" flag was set, then theroutine checks to see if the "motor1" flag also is set at step 806. Ifthe motor1 flag is set, then the routine queries at step 807 whether afire active position sensor contact switch 327) is actuated, whichindicates that trigger pin 312 has moved enough to release compressionspring 210 and a dose of medication. If the switch 327 is not active,then the routine passes to step 808 where the two second alarm ischecked. If the alarm has not expired, the routine passes to step 802for new data. If the alarm has expired, then at step 809 the motor 321is turned off, and the "firing" flag is cleared. The two second alarm isused to preserve battery life. An error may be reported. Optionally, theerror message is displayed on display 15. The routine then passes backto processing data step 802.

If the fire active switch 327 has triggered at step 807, then theroutine passes to step 810 where the motor is turned off, a "motor2"flag is set, the "motor1" flag is cleared, and a * second alarm is set,wherein * is the programmed delay interval. The motor is then turned offfor the programmed delay interval. The interval is selected to providefor complete release of the dose of medication. As noted, this timedepends upon the nozzle dimensions and may be any number ofmilliseconds, e.g., from less than 1/10 of a second to more than 2seconds. Importantly, this provides for delivery of medicationformulations, using a timed (slow) release valve, that are not presentlyobtainable with conventional meter dose devices. For example, use oftimed-release valves and small diameter nozzles (less than 0.018 inch)may improve the delivery of inhaled steroid formulations, i.e., reducingthe amount of drug deposited into the mouth.

Following steps 808, 809, and 810, the routine returns to process newdata at step 802. If at step 806 the "firing" flag is set and the"motor1" flag is not set, then the routine waits for the dose to bedelivered and passes to step 811 where the "motor2" flag is checked. Ifthe "motor2" flag is set, then the routine checks to see if theprogrammed delay * interval has expired at step 812. If it has not, theroutine returns to process new data at step 802. If it has, then theroutine passes to step 813 where the motor is turned on, the "motor3"flag is set, the "motor2" flag is cleared and a 0.5 second alarm is set,and thereafter the routine passes to process the new data at step 802.If at step 811 the "motor2" flag is not set, then the routine checks tosee if the 0.5 second alarm has elapsed at step 814. If it has not, thenthe routine returns to step 802 for new data. If it has, then at step815 the routine turns off the motor, clears the firing flag, clears the"motor3" flag, adjusts the shot counter (decreasing the number ofremaining dosages for and/or increasing the number of doses deliveredby, the given cassette 4), stores the record (e.g., peak flow rate andtotal exhaled volume or the flow rate and flow volume at drug delivery),and returns to obtain new data at step 802.

The selected time interval, for example, 1/2 second, provides sufficienttime for trigger tip 313 to pass out of slot 234 and the release oftorsion spring 220, to reload compression spring 210, and to refill themetered dose chamber of canister 31 following release of the medication.Although not shown in FIG. 19B, device 6 is turned off by rotatingmouthpiece 20 so that contact switch 460 no longer engages location mark44.

Advantageously, the press, controlled hold, and release behavior of thepresent invention provides for the internal metering chamber of metereddose canister 30 to be refilled shortly after releasing the dose ofmedication. This is important because the metering chamber must berefilled, i.e., the canister released, after the canister is agitated.Typically, the patient is instructed to agitate the medication prior torelease of a dose, but that agitation is for filling the chamber for thenext dose.

The precisely timed press and release behavior also ensures reproduciblecanister actuation. It also permits the use of canister nozzlecombinations with a variety of emptying times because the emptying timeparameter, i.e., the hold actuation time, is selectable andprogrammable. It should be understood that persons of ordinary skill inthe art could develop considerably more complicated processes forsensing flow analyzing information and determining when to depress thecanister to release a dose of aerosol medication. Such modifications arebelieved to be within the ability of a person of ordinary skill in theart.

All of the numbers and specific dimensions provided herein areexemplary. It is to be understood that the dimensions can be generallyvaried to obtain the desired release and flow characteristics,specifically different ranges of pressures in the two directions, asdesired.

One skilled in the art will appreciate that the present invention can bepracticed by other than the described embodiments, which are presentedfor purposes of illustration and not of limitation.

We claim:
 1. A hand held device for providing an aerosolized burst of aformulation, comprising:a flow sensor for detecting the inspiratory flowof a patient; a container having a formulation comprised of a drug and acarrier therein and a valve normally biased closed, which valve may beopened when force is applied to a stem of the valve in a directiontoward the container; a drive element for applying force in a manner soas to open the valve; a release actuator for actuating the driveelement; a programmable microprocessor which receives information fromthe sensor and forwards information to the release actuator in order toopen the valve and release aerosolized formulation over a period of timeof from between 10 and 1,000 msec wherein the amount of time isselectable along with relative time with respect to sensor determinedflow rate and flow volume; a visual display; wherein the microprocessoris programmed to determine a patient's pulmonary function and providepulmonary function information to the visual display.
 2. The device ofclaim 1, wherein the microprocessor is programmed to forward informationto the release actuator at a threshold level of inspiratory flow asdetermined by the flow sensor.
 3. The device of claim 1, wherein thepulmonary function measured and displayed is forced expiratory volume inone second.
 4. The device of claim 1, wherein the pulmonary functionmeasured and displayed is forced vital capacity.
 5. The device of claim1, wherein the pulmonary function measured and displayed is peakexpiratory flow rate.
 6. The device of claim 1, wherein the pulmonaryfunction measured and displayed is a display of trend data obtained by acomparison to prior measurements.